Dalia Elfawy., MD Lecturer of Anesthesia and ICU Ain Shams University 2014 RAPID REVERSAL OF...

Dalia Elfawy., MD

Lecturer of Anesthesia and ICU

Ain Shams University

2014

RAPID REVERSAL OF ANTICOAGULATION IN

TRAUMA PATIENTS

OBJECTIVES

• Basic Knowledge about anticoagulants.

• How to reverse anticoagulation in trauma patients.

WHY PEOPLE ARE ON ANTICOAGULANTS

• • Atrial fibrillation

• • Deep vein thrombosis

• • Mechanical heart valves

• • Stroke prevention

• • Heart attacks

• • Heart failure

• • Pulmonary emboli

• • Angina

• • Stents

• • Orthopedic procedures

• • Wound care

TYPES OF ANTICOAGULANTS

WARFARIN

• • Most commonly used oral anticoagulant .

• • Its vit K antagonists Inhibits factors II, VII, IX,

and X formation.

• • Best selling drug

• • Underestimated drug

UNFRACTIONATED HEPARIN (UFH)

• • A glycosaminoglycan that exerts its

anticoagulant effect thru binding and

potentiation of ATIII.

• • Given sub q, IV infusion.

• • Therapy gauged by PTT or INR which is

prolonged.

• • Half-life is 1 hour.

LOW MOLECULAR WEIGHT HEPARIN(LMWH)

• • Has 1/3 the molecular weight of heparin.

• • Has more antifactor Xa activity than inhibition

of thrombin.

• • Does not prolong PTT (since it does not affect

thrombin).

• • Half-life is much longer than heparin and

mainly cleared by the kidneys.

NEWER ANTICOAGULANTS• Direct Thrombin Inhibitors:

• hirudin, lepirudin, desirudin, bivalirudin,

• ximelagatran, Dabigatran

• Xa inhibitors:

• fondaparinux, idraparinux

• Rivaroxaban, Apixaban

ANTIPLATELETSClopidogrel

• It affects the ADP-dependent activation of IIb/IIIa complex.

• Is used to prevent strokes and heart attacks .

• Works by keeping platelets from sticking together and preventing clots.

Glycoprotein IIb/IIIa receptor antagonists

• It block a receptor on the platelet for fibrinogen and von Willebrand factor.

• 3 classes:

Murine-human chimeric antibodies (e.g., abciximab)

Synthetic peptides (e.g., eptifibatide)

Synthetic non-peptides (e.g., tirofiban)

ANTIPLATELETS• Aspirin and Triflusal irreversibly inhibits the

enzyme COX, resulting in reduced platelet production of TXA2 (thromboxane - powerful vasoconstrictor that lowers cyclic AMP and initiates the platelet release reaction).

• Dipyridamole inhibits platelet phosphodiesterase, causing an increase in cyclic AMP with potentiation of the action of PGI2 – opposes actions of TXA2.

INDICATIONS FOR REVERSAL OF ANTICOAGULANTS

• INR above the target range on warfarin.

• Upcoming invasive procedure:

- Bridging.

• Trauma with massive bleeding.

UNIVERSAL CONSIDERATIONS FOR REVERSAL

• How urgent is reversal?

- Faster methods often have drawbacks.

• What is the risk of thrombotic event off

anticoagulation?

- Absolute risk = Rate X Time.

REVERSAL OF WARFARIN

• Choices of antidote:

- Vitamin K.

- FFP.

- Prothrombin complex concentrate (PCC).

- Recombinant activated factor VII (rFVIIa).

REVERSAL OF WARFARIN

• Vitamin K

- Oral administration results in correction by 24

hours.

- IV administration is marginally faster (small

risk of anaphylaxis).

- SC route is unreliable (poor bioavailability).

REVERSAL OF WARFARIN

• FFP

- Each ml contains 1 U of factors II, VII, IX, and X.

- Need large volume for meaningful correction:

dose = (target factor activity – actual level) X body

weight

eg: 20% desired increase X 70 kg = 1400 U or 5-6

bags of FFP.

REVERSAL OF WARFARIN

• PCC

- 3-factor concentrate contains only II, IX and X.

- 4-factor version was just approved in the USA.

At least equivalent of FFP for stopping major bleeding at

24 hours.

Superior for INR reduction (<1.3) at 30 min.

Less volume (105 mL +/- 37 mL versus 865 mL +/- 269

mL).

REVERSAL OF WARFARIN

• rFVIIa

- Approved indications include hemophilia A or B with

inhibitor, congenital factor VII deficiency and acquired

hemophilia.

- “Bypassing” effect helps sustain coagulation in the

absence of FVIII or FIX.

- Does correct deficit in factors II, IX and X.

- Corrects the INR.

- Doses used have varied (20-90 mcg/Kg).

GUIDELINES FOR WARFARIN REVERSAL

• ACCP 2012 guidelines for warfarin overanticoagulation (No bleeding):

- INR < 4.5

Decrease the dose of warfarin.

- INR 4.5 – 10

Hold warfarin

Can administer small dose of vitamin K (not routinely)

- INR > 10

Administer oral vitamin K.

GUIDELINES FOR WARFARIN REVERSAL

• ACCP 2012 guidelines for warfarin reversal

(major bleeding present)

- IV vitamin K

- First choice for immediate reversal (over FFP):

4-factor PCC.

GUIDELINES FOR WARFARIN BRIDGING

• ACCP 2012 Guidelines

- High thrombotic risk (atrial fibrillation CHADS2 score 5 or 6, recent stroke, TIA, Rheumatic valvular heart disease, recent venous thromboembolism, protein C,S deficiency): bridge.

- Moderate thrombotic risk ( atrial fibrillation CHADS2 score 3 or 4, old venous thromboembolism, active cancer): use clinical judgment (consider risk of bleeding)

- Low thrombotic risk ( atrial fibrillation CHADS2 score 0 to 2, previous venous thromboembolism of more than 12 months): do not bridge.

GUIDELINES FOR WARFARIN BRIDGING

• ACCP 2012 guidelines

- Last dose of warfarin 5 days before the surgery.

- Parenteral anticoagulant:

• Last dose of LMWH should be 24 hours before the surgery.

• Last dose of IV UFH 4-6 hours before the surgery.

• Restart 24-72 hours.

- Restart warfarin 12-24 hours after the procedure.

REVERSAL OF IV UFH• Protamine

- Binds heparin chains.

- Administer 1 mg of protamine per 100 U of circulating heparin.

Time Elapsed

Dose of Protamine (mg) to neutralize 100 units of heparin

Immediate 1-1.5

30-60 min 0.5-0.75>2 h 0.25-0.375

REVERSAL OF UFH• Protamine

- Excess amount acts as a mild anticoagulant.

- Risk of infusion reaction:

• Hypotension/circulatory collapse.

• Pulmonary edema.

• Pulmonary hypertension.

REVERSAL OF LMWH• Protamine

- Neutralizes about 60-75% of activity

- consider half life of enoxaparin

Enoxaparin administered < 8 hours prior: give 1 mg of protamine per mg of enoxaparin.

Enoxaparin administered >8 hours prior: give 0.5 mg of protamine per mg of enoxaparin.

REVERSAL OF DABIGATRAN

• Activated charcoal if ingestion < 2 hours prior.

• Hemodialysis can help clear the drug ( low binding

to plasma protein)

- Useful for patient with renal failure.

• aPCC: takes long time.

• rFVIIa: partial correction of thrombin generation.

REVERSAL OF RIVAROXABAN

• Activated charcoal if ingestion < 2 hours prior.

• 4-factor PCC.

• aPCC: takes long time.

• rFVIIa: partial correction of thrombin

generation.

RECENT ADVANCES

• Monoclonal antibody directed against dabigatran

showed efficacy in murine model.

• PRT4445 universal reversal agent for Xa inhibitors

drug neutalizes the effect of enoxaparin and

fondaparinux in rats ,rapid (5 min) and sustaned (3

h) effect.

• PER977 is synthetic molecule binds to NOACs

(dabigatran and rivaroxaban).

PROTOCOL FOR REVERSAL OF ANTIPLATELETS

• Patients presenting with an intracranial hemorrhage on ASA

alone are given 5 platelet concentrate units upon admission.

• Patients presenting with an acute ICH on clopidogrel with

small hemorrhages an initial transfusion of 10 platelet

concentrate units upon admission.

• Patients with a severe acute ICH on clopidogrel, 10 units of

platelets are transfused initially with 0.3µg/kg of

desmopressin, and platelets are subsequently transfused

every 12 hours for the next 48 hours.

DESMOPRESSIN

• Is a synthetic analogue of antidiuretic hormone.

• Increasing plasma levels of Factor VIII is

beneficial for patients with hemophilia and von

Willebrand’s disease.

• is effective for patients with qualitative platelet

defects by reversing the antiplatelet effects of

glycoprotein IIb/IIIa inhibitors and aspirin therapy.

QUIZ

• Warfarin works mainly through inhibition of thrombin

• True

• False

• Oral administration of vitamin K helps in reversal of warfarin effect within 2 hours

• True

• False

• APCC is useful in clearing Dabigatran• True

• False

• Protamine neutralizes about 60-75% of LMWH activity

• True

• False

THANK YOU